The major objectives of this proposal are: 1. to quantitatively assess the relative contribution of brain adaptation and increased metabolic disposition in the development of tolerance to barbituates. We have demonstrated that central tolerance can be abolished by intracerebroventricular (icv) injection of hemicholinium-3 (HC) or ip atropine. Non-sedative hepatic enzyme inducers (phenylbutazone) will be used to produce metabolic but not central tolerance. The effect of tolerance on the distribution and binding of barbituates to brain subfractions and on clearance of the barbiturates from the CNS will also be explored. 2. to determine the role of brain neurotransmitters in the production of tolerance by examining the relationship between the effect on tolerance of atropine, physostigmine, HC and 6-hydroxydopamine and the levels and/or turnover of acetylcholine and catecholamines in discrete brain regions. 3. to explore the influence of protein and nucleic acid inhibitors on the production of tolerance. BIBLIOGRAPHIC REFERENCE: Lyness, W.H. and M.J. Mycek, "Clearance of Centrally Administered Phenobarbital (Pb) in Tolerant and Nontolerant Rats", Fed. Proceeding, April, 1977.